The primary focus of R01DA016078 is the progression of hepatitis C virus (HCV)-related liver disease in HIV-infected persons. In the United States, HCV-related liver disease is one of the leading causes of death among HIV infected persons and occurs chiefly among persons who have injected illicit drugs (IDUs). However, the degree to which HIV infection increases HCV liver disease risk among IDUs has not been characterized and the mechanisms of how HIV affects liver disease are largely unknown. The major limitation of liver disease research among IDUs is measurement of disease stage. Recently, this challenge has been overcome. We have shown in IDUs that liver disease can be accurately and safely measured by assessment of liver stiffness by elastography. In our first aim, we use this method to test the hypothesis that HIV-related CD4 + lymphocyte depletion accelerates progression of liver disease among HCV-infected IDUs and to characterize the magnitude of that effect. Ultimately, HCV-related liver disease causes mortality when there is liver failure, or end stage liver disease. In our second aim, we ask whether measurements of liver stiffness affect the risk of developing liver failure among IDUs and characterize this risk. Although ongoing HCV replication is necessary for HCV-related liver disease progression, it is not clear whether the risk of progression is affected by the degree of replication (as has been shown with other chronic viral infections). HIV infection increases the serum level of HCV RNA, but it is unclear why this occurs and whether it is associated with greater disease progression. Our third aim is to test the hypothesis that greater HCV proliferation increases the risk of liver disease progression and to examine whether the risk is altered by HIV-infection or CD4+ lymphocyte depletion. By using our repository of serum and liver tissue, we will be able to test this hypothesis by investigating HCV RNA replication in serum and in specific liver cells dissected by laser capture microscopy. A high likelihood of success is anticipated in this research program as an experienced, cohesive team will continue to use available technology and well characterized human tissues to understand HCV related liver disease progression in HIV infected persons